It is known that magnetic particles (‘beads’) embedded in a liquid can be used to carry a probe molecule on their surface that specifically interacts with a complementary target molecule (for example single stranded probe DNA interacting with complementary target DNA). Upon reaction with a molecule to be probed and, for example, using optical or electrochemical measurements, one can determine the amount of target molecules on a bead or within a certain volume containing beads (see for example Hsueh et al., Techn. Digest Transducers '97, p. 175 (1997)). The interest in using magnetic microbeads, is that they can be manipulated using magnetic fields irrespective of fluid motion. In this way one can create an important relative motion of the beads with respect to the fluid and, hence, a large probability of binding a target molecule to a probe molecule fixed on the bead surface. One can then magnetically extract the beads to a place of detection/collection. Historically, beads have been locally fixed by using external magnets or have been transported using mechanically moving external magnets. The latter procedure may be for example used to fabricate mixing devices (Sugarman et al., U.S. Pat. No. 5,222,808) and in immuno-assay methods (Kamada et al., U.S. Pat. No. 4,916,081).
“Separation” of magnetic microbeads means that a liquid flow, containing the beads, passes a zone with a large magnetic field (gradient) and that the magnetic microbeads are filtered out (separated) by the field. U.S. Pat. No. 5,779,892 describes the use of a permanent magnet to separate (filter) the magnetic microbeads from a passing liquid solution. U.S. Pat. No. 6,013,188 describes a ferromagnetic capture structure, made of a Ni grid and placed in the field of a permanent magnet to select magnetic microbeads from a liquid solution that passes through the grid. Other patents on separation of magnetic beads are U.S. Pat. No. 6,132,607 and the US patents mentioned therein. Finally, U.S. Pat. No. 6,193,892 describes how a rack that is to hold containers with magnetically responsive solutions is configured with permanent magnets to extract the magnetic microbeads from the solution. U.S. Pat. No. 5,541,072 concerns the creation of magnetic clusters (ferrophases) that are transported by a permanent magnet. Ahn et al. [C. H. Ahn, M. G. Allen, W. Trimmer, Y. J. Yun, and S. Erramilli, J. Microelectromechanical Syst. 5, 151-158, 1996] have reported magnetic bead separation device using integrated inductive components; in follow-up work, electroplated spiral coils in Cu were combined with an electroplated permalloy yoke structure to separate microbeads from a liquid solution passing over an array of coils [J.-W. Choi, T. M. Liakopoulos, and C. H. Ahn, Biosens. & Bioelectronics 16, 409-416, 2001]. The coils were arranged spaced apart from one another side-by-side. As the magnetic field is localised over an area of the order of the coil width, the described simple juxtaposition of the coils will not enable microbead transport, but merely allow separation of the microbeads. With this proposal, the microbeads were retained and separated by action of a magnetic field generated by the coil, but it was not possible to transport the beads by the action of the magnetic field. Transporting the beads required using a liquid flow.
Magnetic transport of beads is essential for bringing the beads to a well-defined position within a microfluidic circuit, for example near to a magnetic bead detection device. “Transport” means that the microbeads are effectively moved by a magnetic force, i.e. using a magnetic field and not just retained by a magnetic field from a liquid solution passing by (=separation). Nevertheless, manipulation of these beads in general and transport in particular, is a difficult task, as the effective relative magnetic susceptibility χeff of the (super)paramagnetic beads is rather weak (typically χeff<<1, due to demagnetization effects of the mostly spherical particles) and the magnetic volume of the particles is small. This explains why mostly the large field of (mechanically moving) permanent magnets or large electromagnets have been used for the separation, transport, and positioning of magnetic microbeads [See webpage of Miltenyi Biotec Inc., Auburn, Calif.: http://www.miltenyibiotec.com.; S. Østergaard, G. Blankenstein, H. Dirac, and O. Leistiko, J. Magn. Magn. Mat. 194, 156-162, 1999 and WO 99/49319]. In other work, micropatterned conductors, actuated by large currents, have been demonstrated to present a useful solution for magnetic microbeads capture and transport. These devices allow precise positioning and transport over 10-100 μm distances in a single actuation event [T. Deng, G. M. Whitesides, M. Radhakrishnan, G. Zabow, and M. Prentiss, Appl. Phys. Lett. 78, 1775-1777, 2001; C. S. Lee, H. Lee, and R. M. Westervelt, Appl. Phys. Lett. 79, 3308-3310, 2001].
In the work of Deng et al., the field of a permanent magnet placed at some distance beneath the device has been combined with the field generated by the current through an electrical conductor. Here, the electrical conductor was made of two side-by-side serpentine wires shifted linearly in phase by π/3, that generated a magnetic field having local field maxima in every turn and with opposite directions in neighbouring turns. However, the generated magnetic field gradient (several 0.1 T/mm) is localized over a small distance (˜100 μm) which leads to the consequence that many actuation steps are necessary to transport beads through a large surface area rapidly. This disadvantage is particularly serious for application in biotechnology, where it is desirable to rapidly transport beads over distances of several millimetres which requires several hundreds of actuation steps with this serpentine wire arrangement. Also the magnetic field generated by a single wire is weak, so that large currents (of the order of 106 A/mm2) are required to transport the microbeads over these small distances.
WO 02/31505 describes the use of an electromagnetic chip to transport and detect the presence of magnetic beads.
In previous work on magnetic bead transport, the moving magnetic field is obtained by mechanically moving a permanent magnet (magnetic induction of the order of 0.1-1.5 Tesla), which is a very large value that can induce an important magnetic moment in the microbead (the magnetic moment is given by μ=VχeffB0, with B0 the magnetic field generated by the permanent magnet, χeff the magnetic permeability and V the magnetic microbead volume). One should realize that a very small microbead has no effective magnetization when there is no external field, ie it is superparamagnetic. The magnetic force on such moment in a total magnetic induction field B is given by:
                    F        =                              μ                          μ              0                                ⁢                      ∇            B                                              (        1        )            making it clear that a strong magnetic force is obtained when having a large moment AND a large gradient of the magnetic induction. To have appreciable magnetic forces, relatively important magnetic fields (about 10−2 T) and large magnetic field gradients (from 10 to 100 T/m) must be generated locally [G. P. Hatch, and R. E. Stelter, “Magnetic design considerations for devices and particles used for biological high-gradient magnetic separation (HGMS)”, J. Magnetism Magn. Materials 225, pp. 262-276, 2001]. A permanent magnet hence delivers a large force, but the problem is that it is cumbersome in generating a ‘moving’ field.
On the other hand, the magnetic field generated by a coil fed with a current can be varied in time easily but is very small. Typically fields of just a few milliTesla are generated by a simple coil using currents of the order of 0.1-1 Amp. When looking at equation (1), it is clear that the magnetic moment of the microbead will be typically a factor 1000 smaller and that also the magnetic gradient will be a factor 10 smaller. The consequence is that magnetic forces of coils can be easily varied in space and time but that the forces are too small to effectively transport the microbeads. An improvement would be to fabricate a magnetic yoke structure made of a soft magnetic material around the coil, which amplifies somewhat the magnetic field that is generated by the coil (typically a factor 10).
However, the prior art does not disclose any effective way of using simple coils to displace magnetic beads.